{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:30:08Z","timestamp":1768509008550,"version":"3.49.0"},"posted":{"date-parts":[[2023,10,5]]},"group-title":"Biochemistry","reference-count":56,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2023,10,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Choline is an essential nutrient that the human body needs in vast quantities for cell membrane synthesis, epigenetic modification, and neurotransmission. The brain has a particularly high demand for choline, but how it enters the brain has eluded the field for over fifty years. The MFS transporter FLVCR1 was recently determined to be a choline transporter, and while this protein is not highly expressed at the blood-brain barrier (BBB), its relative FLVCR2 is. Previous studies have shown that mutations in human\n                  <jats:italic>Flvcr2<\/jats:italic>\n                  cause cerebral vascular abnormalities, hydrocephalus, and embryonic lethality, but the physiological role of FLVCR2 is unknown. Here, we demonstrate both\n                  <jats:italic>in vivo<\/jats:italic>\n                  and\n                  <jats:italic>in vitro<\/jats:italic>\n                  that FLVCR2 is a BBB choline transporter and is responsible for the majority of choline uptake into the brain. We also determine the structures of choline-bound FLVCR2 in the inward- and outward-facing states using cryo-electron microscopy to 2.49 and 2.77 \u00c5 resolution, respectively. These results reveal how the brain obtains choline and provide molecular-level insights into how FLVCR2 binds choline in an aromatic cage and mediates its uptake. Our work could provide a novel framework for the targeted delivery of neurotherapeutics into the brain.\n                <\/jats:p>","DOI":"10.1101\/2023.10.05.561059","type":"posted-content","created":{"date-parts":[[2023,10,5]],"date-time":"2023-10-05T23:20:38Z","timestamp":1696548038000},"source":"Crossref","is-referenced-by-count":3,"title":["Structural and molecular basis of choline uptake into the brain by FLVCR2"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4503-002X","authenticated-orcid":false,"given":"Rosemary J.","family":"Cater","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7980-6741","authenticated-orcid":false,"given":"Dibyanti","family":"Mukherjee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4046-5756","authenticated-orcid":false,"given":"Eva Gil","family":"Iturbe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8694-7681","authenticated-orcid":false,"given":"Satchal K.","family":"Erramilli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Chen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katie","family":"Koo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8919-833X","authenticated-orcid":false,"given":"Nicol\u00e1s Santander","family":"Grez","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrew","family":"Reckers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0130-8739","authenticated-orcid":false,"given":"Brian","family":"Kloss","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7906-0097","authenticated-orcid":false,"given":"Tomasz","family":"Gawda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Brendon C.","family":"Choy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhening","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Oliver B.","family":"Clarke","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8121-8746","authenticated-orcid":false,"given":"Sook Wah","family":"Yee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3174-9359","authenticated-orcid":false,"given":"Anthony A.","family":"Kossiakoff","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8620-827X","authenticated-orcid":false,"given":"Matthias","family":"Quick","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7310-5597","authenticated-orcid":false,"given":"Thomas","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3293-2200","authenticated-orcid":false,"given":"Filippo","family":"Mancia","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2023101102200771000_2023.10.05.561059v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1753-4887.2009.00246.x"},{"key":"2023101102200771000_2023.10.05.561059v1.2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.nutr.26.061505.111156"},{"key":"2023101102200771000_2023.10.05.561059v1.3","unstructured":"Institute of Medicine (US) Standing Committee on the Scientific Evaluation of Dietary Reference Intakes and its Panel on Folate, Other B Vitamins, and Choline. 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